The objective of this renewal is to respond to two commonly observed clinical problems in temporomandibular joint (TMJ) disease by engineering a biomimetic TMJ disc complex. This will subsequently be implanted in a porcine animal model. The overall hypothesis is that the implantation of an anatomically-shaped, robust TMJ disc, engineered with attachments and containing appropriate matrix anisotropy, will be able to address TMJ disc perforation (via a patch approach) and TMJ disc lateral defects (via a subtotal approach). The following three specific aims are proposed to test this hypothesis: 1) to characterize the bulk and interfacial properties of the discal attachments, 2) to engineer an anatomically-correct TMJ disc with attachments, and 3) implant this engineered TMJ disc complex in a porcine animal model with clinically representative in vivo defects. While in the previous grant the properties of the TMJ disc were investigated to inform the engineering of the TMJ disc, collaboration with TMJ surgeons has highlighted the functional importance of the disc attachments. Aim 1 will inform the engineering of the TMJ disc and attachments for Aim 2, by characterizing the biochemical composition, biomechanical properties, and cellular population of the disc attachments and interface. The previous grant also identified the need for a biological TMJ disc replacement to match the native tissue shape and organization. It also recognized the costal cartilage as an alternative cell source for TMJ disc engineering. Therefore, Aim 2 will use this cell source to generate robust constructs with anisotropic features for implantation in Aim 3, and the properties of this TMJ disc complex will be modified using ion channel modulators, a matrix remodeling enzyme, and a tension-compression bioreactor. Finally, Aim 3 will devise methods to surgically access the TMJ, and for the first time, implant and secure an engineered TMJ disc complex in vivo, to fill clinically relevant TMJ disc defects in a porcine model. This proposal seeks to: 1) characterize the discal attachments and their function in the TMJ, to 2) inform the tissue engineering of a functional biological replacement TMJ disc complex, and 3) develop a surgical approach to implant this replacement. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page PUBLIC HEALTH RELEVANCE: Epidemiologic surveys indicate that 20-25% of the general population have symptoms of TMJ disorders (TMDs), with the onset of severe TMDs most prevalent in women ages 20 to 40. Due to the young patient population, there is an immense need for long term clinical solutions to TMDs. Unlike other musculoskeletal problems, there is a clear shortage of treatment options between the onset of TMDs and total joint replacement for severe disease. The objective of this project is to continue work toward elucidating TMJ structure-function relationships and tissue engineering a functional TMJ disc that also includes its attachments. Following a systematic approach, employing exogenous agents and the development of cogent surgical approaches, the tissue engineered TMJ disc complex will be investigated in vivo. Addressed will be two commonly observed clinical pathologies, perforations in the central portion of the disc and damage in the lateral regions of the intermediate zone. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page